Typical antibody drug conjugates (ADC) contain monoclonal antibodies capable to bind to surface specific antigens of cancer cells. These antibodies include some proteins on the surface of immune system B cells and T cells, such as CD20, CD22, and human epidermal growth factor receptor 2 (Her2) and prostate specific membrane antigen (PSMA). These antibodies are connected with the highly toxic drugs through a cleavable linker unit. Drugs are designed to induce irreversible DNA damage or interfere with cell division, so as to lead to apoptosis of cancer cells.
The mechanism of antibody drug conjugates (ADC) is to recognize and bind to specific antigen through the antibodies, trigger a series of reactions, and then enter the cytoplasm through the endocytosis, where the highly toxic drug is dissociated from the lysosomal enzymes to kill cancer cells. Compared with the traditional chemotherapy which causes damage to both cancer cells and normal tissues indiscriminately, targeting drug delivery can make the drug act on cancer cells directly and reduce the damage to normal cells.
The first antibody drug conjugate approved by the FDA is Mylotarg (gemtuzumab/ozogamicin), developed by Wyeth in 2000 for the treatment of acute myeloid leukemia, but due to some adverse effects and safety consideration, the drug was withdrawn after ten years. Since then, much progress has been made in the technology of linking antibodies and drugs. By using a linker with a proper biological half-life, researchers are able to ensure that the antibody drug conjugate can reach target cells thereby reducing side effects.
In 2011, Adcetris (brentuximab vedotin) from Seattle Genetics was approved by the FDA for the treatment of Hodgkin's lymphoma and systematic anaplastic large cell lymphoma. The turnover of the antibody drug conjugate in the first quarter of 2012 reached $34,500,000 and continued increasing. It is expected that in the next ten years, the use of antibody drug conjugates will be increased by about 50% in cancer therapy drug market. At present, Roche and Genentech together have more than 25 antibody drug conjugates in the research and development, of which 9 are in clinical research.
The first antibody drug conjugate, a potential blockbuster, Kadcyla (trastuzumab emtansine, T-DM1) was approved on sale for the treatment of metastatic breast cancer in February 2013. Kadcyla was formulated by combining Herceptin which is an antibody used for the treatment of breast cancer with a toxin Maitansine licensed by ImmunoGen. The turnover of the drug in 2015 was nearly 700 million dollar.
Antibody drug conjugates are likely to become the next resounding drug field that will bring sustained income. The collaboration of biomedicine and clinical trials results in continuous success of antibody drug conjugate technology. These common results suggest the use of humanized monoclonal antibody technology as target directed therapeutic delivery. So far, most of the antibody drug conjugates that have been developed are using auristatins supplied by Seattle Genetics or maytansine supplied by ImmunoGen as effective toxins. In addition, Spirogen and other companies are also developing other toxins for the next generation of antibody drug conjugates, such as class PBD.
Maytansinoids alkaloid was first isolated from Maytenus serrata, a shrub in East African (US 389611, JP 01006282, JP 63233986), which is a compound with high cytotoxicity used as an anti-cancer agent. Many maytansine derivatives prepared artificially with high anticancer activity are 100 to 1000 times that of traditional anticancer drugs, such as vincaleukoblastinum or taxinol. (J. Med. Chem., 1978, 21, 31-37, Chem. Pharma. Bull., 1984, 3441-3451, J. MAed. Chem. 2006, 49, 4392-4408, Chem. Pharm. Bull. 2004, 52 (1) 1-26, WO 2011039721, WO 2012/061590, WO 2014/094453).
In patent documents U.S. Pat. Nos. 5,208,020, 5,416,064 and J. Med. Chem, 2006, 49, 4392-4408, Chari, R. V. J. et al. reported the maytansine analogues DM1 and DM4. Patent application WO 2004/103272, EP 0425235 reported the conjugates of maytansine analogues DM1 and DM4 and anticancer activities thereof. A series of articles and patents followed reported many conjugates of maytansine analogues used as antitumor drugs (WO 2011/039721, WO 2012/061590, WO 2014/134483, WO 2014/134457, WO 2014/194030, WO 2014/134486, WO 2014/094355, WO 2015/000062, WO 2014/145090, WO 2013/173391).
Typical antibody drug conjugate is comprised by three parts of a drug, a linker unit and an antibody. The choice of specific antibody and drug depends on specific diseases and has important effects on the safety and efficacy of the conjugate. The stability of the linker unit and the coupling method to the antibody play a decisive role in the development of ADC drug. Factors that determine the efficacy of antibody drug conjugates include the stability and fracture sensitivity of the linker unit, cell surface excitation internalization, transport, and release of the cytotoxin.

T-DM1, for example, is prone to degrade and release toxins prematurely before antigen binding protein (Abu) begins endocytosis, thereby causing side effects. Moreover, the drug/antibody ratio of T-DM1 is relatively low, and the distribution is greatly varied, and it is difficult to control the efficacy and safety precisely (WO 2012/061590 A1, WO 201139721). Therefore, the technical problem required to be solved is to search a linker with high stability and good water-solubility, thereby obtaining an antibody drug conjugate with high release efficiency of cytotoxin, high specificity, high cytotoxicity, good anti-cancer effect.